Clinical sequencing defines the somatic and germline mutation landscapes of Chinese HER2-Low Breast Cancer.

More than half of the breast cancer initially labeled as human epidermal growth factor receptor 2 (HER2)-negative actually exhibited low HER2 levels (IHC 1+ or IHC 2+/FISH-) and were classified as HER2-low breast cancer. Previous research emphasized the significant biological heterogeneity in HER2-low breast cancer, highlighting the importance of accurately characterizing HER2-low tumors to promote the precise management of antibody‒drug conjugates. In this study, we established a large-scale targeted sequencing cohort (N = 1907) representing Chinese HER2-low breast cancer patients with detailed clinical annotation. Our research findings revealed that HER2-low breast cancer demonstrated distinct clinical pathological characteristics and mutation landscapes compared to HER2-zero group. When compared to HER2-zero tumors, HER2-low tumors exhibited a higher proportion of Luminal B subtypes and better disease-free survival. In hormone receptor (HR)-positive breast cancer, HER2-low group showed a higher frequency of GATA3 somatic mutations, BRCA2 germline mutations, and mutations in the DNA damage repair pathway. In contrast, in HR-negative breast cancer, the HER2-low group displayed a higher frequency of PIK3CA mutations and PI3K pathway alterations. These findings offered valuable insights for the precise targeted treatment of HER2-low breast cancer in different HR statuses.

HNRNPU promotes the progression of triple-negative breast cancer via RNA transcription and alternative splicing mechanisms.

Triple-negative breast cancer (TNBC) is a great detriment to women's health due to the lack of effective therapeutic targets. In this study, we employed an integrated genetic screen to identify a pivotal oncogenic factor, heterogeneous nuclear ribonucleoprotein U (HNRNPU), which is required for the progression of TNBC. We elucidated the pro-oncogenic role of HNRNPU, which can induce the proliferation and migration of TNBC cells via its association with DEAD box helicase 5 (DDX5) protein. Elevated levels of the HNRNPU-DDX5 complex prohibited the intron retention of minichromosome maintenance protein 10 (MCM10) pre-mRNA, decreased nonsense-mediated mRNA decay, and activated Wnt/ß-catenin signalling; on the other hand, HNRNPU-DDX5 is located in the transcriptional start sites (TSS) of LIM domain only protein 4 (LMO4) and its upregulation promoted the transcription of LMO4, consequently activating PI3K-Akt-mTOR signalling. Our data highlight the synergetic effects of HNRNPU in RNA transcription and splicing in regulating cancer progression and suggest that HNRNPU may act as a potential molecular target in the treatment of TNBC.

Clinicopathological Characteristics and Survival Outcomes of Mammary Paget's Disease: A Retrospective Study Based on a Chinese Population.

BACKGROUND: Mammary Paget's disease (PD) is a rare type of breast cancer. Most cases of PD are presented with underlying ductal carcinoma in situ (DCIS) or invasive breast carcinoma (IDC). This study aimed to investigate the clinicopathological characteristics and survival outcomes of PD patients. MATERIALS AND METHODS: A total of 406 patients diagnosed with PD with IDC/DCIS at Fudan University Shanghai Cancer Center (FUSCC) were recruited as the PD group, 1218 patients diagnosed with IDC/DCIS alone during the same period were selected as the non-PD group, and the clinicopathological results of these two groups were compared. The Surveillance, Epidemiology, and End Results (SEER) database was used to investigate the clinicopathological features between PD and non-PD patients for validation. RESULTS: Compared with the non-PD group, the PD group was much more likely to have larger (≥2 cm: 43.1% vs 35.5%, P < 0.001), less hormone receptor (HR)-positive (68.5% vs 26.6%, P < 0.001), more human epidermal growth factor receptor-2 (HER-2)-positive (70.7% vs 27.5%, P < 0.001) and higher Ki-67 proportion (51.5% vs 42.5%, P < 0.001) tumors. The HER-2 overexpression subtype accounted for the largest proportion in the PD-IDC group and the lowest proportion in the non-PD-IDC group (54% vs 8%, P < 0.01). Moreover, the PD group had significantly worse disease-free survival (DFS) than the non-PD group (5-year DFS: 91.8% vs 97.3%, P = 0.001), and the SEER database showed a similar trend. Univariate and multivariate Cox regression analyses demonstrated that PD was an independent poor-risk factor. Our matched study showed that the PD group had worse survival than the non-PD group after excluding age, HR, HER-2, tumor size and lymph node status. CONCLUSION: PD with IDC/DCIS is associated with more aggressive tumor characteristics and worse survival outcomes. More than half of PD breast cancers are HER-2 overexpression subtype. PD is an independent poor-risk factor for breast cancer survival.

Clinical features and survival of pregnancy-associated breast cancer: a retrospective study of 203 cases in China.

BACKGROUND: Pregnancy-associated breast cancer (PABC) is an aggressive disease, and since Chinese authority began to encourage childbearing in 2015, the incidence of PABC has increased. This study investigated the characteristics and survival of PABC patients. METHODS: Patients with PABC who underwent surgery at Fudan University, Shanghai Cancer Center between 2005 and 2018 were enrolled. Data concerning the tumor characteristics, maternal state (whether first or non-first pregnancy) and survival outcome were recorded. Pearson Chi-square tests were used to compare the characteristics of the tumors, and Kaplan-Meier methods were used to perform the survival analysis. RESULTS: Overall, 203 PABC patients were recruited. Since 2015, 65.5% of non-first pregnant women were diagnosed with breast cancer, it's 5.7 fold of the incidence of PABC in non-first pregnant women. No significant differences in tumor characteristics were observed between the patients who were in their first pregnancy and those in non-first pregnancy. Among the entire PABC population, luminal B breast cancer accounted for the largest proportion (38.4%), followed by triple-negative breast cancer (TNBC, 30.0%). The distribution of the molecular subtypes of PABC and non-PABC differed (P < 0.001) as follows: in the PABC patients, Luminal B 38.4%, Triple negative breast cancer (TNBC) 30.1%, Human Epidermal Growth Factor Receptor 2 (HER-2) overexpression 15.8%, and Luminal A 10.8%; in the non-PABC patients, Luminal A 50.9%, Luminal B 20.1%, TNBC 17.4%, and HER-2 overexpression 8.0%. The 3-year disease free survival (DFS) of all PABC patients was 80.3%. The 3-year DFS of the patients in the first-pregnancy group was 78.4%, and that of the patients in the non-first-pregnancy group was 83.7% (P = 0.325). CONCLUSIONS: Our study proved that the proportion of women who developed PABC during the second or third pregnancy was extremely high relative to the newborn populations. The patients in the PABC population tended to present more luminal B and TNBC breast cancer than the non-PABC patients.